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National Academy of Sciences Paper: Dartmouth researchers take novel approach to fighting treatment-resistant chronic myeloid leukemia

Hanover, N.H.—In a paper published in the Proceedings of the National Academy of Sciences, researchers at Dartmouth's Geisel School of Medicine described a novel approach to killing chronic myeloid leukemia (CML) cells without harming normal cells, an approach that could help fight off the disease in patients who have developed resistance to standard treatment.

The study, led by Manabu Kurokawa, PhD, assistant professor of pharmacology and toxicology at the Geisel School of Medicine, centered on the research team taking an inventive path to kill chronic myeloid leukemia (CML) cells.

"CML is a unique cancer because it is well established that an oncoprotein called BCR-ABL causes the disease, and healthy individuals do not have the BCR-ABL oncoprotein," said Kurokawa. "Usually, we try to inhibit the activity of BCR-ABL—by using drugs such as Imatinib—so that CML cells die. Unfortunately, though, sometimes CML cells escape this drug by acquiring resistance, which leads to poor prognosis.

Kurokawa continued, "However, in our study, we found a new way to kill CML cells, by harnessing BCR-ABL activity, instead of inhibiting it, in order to cause cancer cell death. Using this approach, the presence or absence of drug-resistant mutations does not matter because the special gene therapy construct we developed kills the cancer cells as long as there is BCR-ABL activity, which normal cells do not have.

"One interesting approach using this technique may be to 'clean' the patient's bone marrow, where drug-resistant CML stem cells might otherwise still exist, and perform autologous bone marrow transplant for the patient who cannot find a matched donor.

"That said, it will still require multiple steps to translate this discovery to new treatments, but we at least showed a proof of concept for the first time," said Kurokawa.

Below is the abstract from Kurokawa's study in the 2013 Proceedings of the National Academy of Science. To read the full paper, click here.

Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells

Increased understanding of the precise molecular mechanisms involved in cell survival and cell death signaling pathways offers the promise of harnessing these molecules to eliminate cancer cells without damaging normal cells. Tyrosine kinase oncoproteins promote the genesis of leukemias through both increased cell proliferation and inhibition of apoptotic cell death. Although tyrosine kinase inhibitors, such as the BCR-ABL inhibitor Imatinib, have demonstrated remarkable efficacy in the clinic, drug-resistant leukemias emerge in some patients because of either the acquisition of point mutations or amplification of the tyrosine kinase, resulting in a poor long-term prognosis. Here, we exploit the molecular mechanisms of caspase activation and tyrosine kinase/adaptor protein signaling to forge a unique approach for selectively killing leukemic cells through the forcible induction of apoptosis. We have engineered caspase variants that can directly be activated in response to BCR-ABL. Because we harness, rather than inhibit, the activity of leukemogenic kinases to kill transformed cells, this approach selectively eliminates leukemic cells regardless of drug-resistant mutations.

The Geisel School of Medicine at Dartmouth, founded in 1797, strives to improve the lives of the communities it serves through excellence in learning, discovery, and healing. The nation's fourth-oldest medical school, the Geisel School of Medicine has been home to many firsts in medical education, research and practice, including the discovery of the mechanism for how light resets biological clocks, creating the first multispecialty intensive care unit, the first comprehensive examination of U.S. health care cost variations (The Dartmouth Atlas), and helping establish the first Center for Health Care Delivery Science, which launched in 2010. As one of America's top medical schools, Dartmouth's Geisel School of Medicine is committed to training new generations of diverse health care leaders who will help solve our most vexing challenges in health care.

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Contact: Derik Hertel, 603-650-1211 or derik.hertel@dartmouth.edu

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